Epithelial cells-require correct polarization and patterning for their function. Epithelial tissues are often polarized in two axes, in the apical-basolateral axis and in the plane of the epithelium. Planar polarization in vertebrates is evident in the skin or internal organs, like the inner ear epithelium with its sensory cilia, and in insects in the cuticular structures and the compound eye. The precise polarization patterns in Drosophila, and the photoreceptor arrangement in the retina in particular, serve as a paradigm to study epithelial planar polarity determination and coordination of polarized cell shape changes in general. The Frizzled (Fz) receptor and its signaling cascade serve as an entry point to study the molecular aspects controlling these processes. The underlying Fz signaling pathway is conserved throughout evolution and also regulates several other aspects of coordinated cellular polarization in vertebrates and invertebrates. Fz mediated planar polarity signaling is distinct from the canonical Wnt/Fz/beta-catenin pathway and its components are only now being identified. Moreover, the link between Fz/planar polarity signaling and the resulting cellular responses including specific transcriptional events are not understood. Whereas the canonical Wnt/Fz/beta-catenin pathway inhibits photoreceptor differentiation, the distinct Wnt/Fz/planar polarity signaling is essential for the correct arrangement of the photoreceptors. The scope of this application is to (1) identify genes required in Fz mediated photoreceptor polarization and (2) define their specific roles in planar polarity determination. Their function in Fz signaling and in cellular polarization events will be investigated. A combination of genetic and functional in vivo studies in Drosophila will be utilized to achieve these goals. Planar polarization and Fz signaling have been linked to medical abnormalities (including deafness/inner ear epithelium) and cancer (as components of the pathway are proto- oncogenes or tumor suppressors). The information acquired in this proposal will both advance our understanding of eye patterning, and will also be of medical relevance.